A drug that activates only your father’s version of a gene may treat neural disorder

A drug that activates the normally silenced paternal copy of a gene may help …

Anyone who's passed basic biology knows that we get one copy of a gene from our mother, a second from our father. But few people realize that not all of these genes end up being treated equally. Imprinted genes are expressed from only the maternal or paternal allele, rather than both. And, when this process goes wrong, it can actually lead to diseases. Now, researchers have identified a possible way to treat imprinting errors.

In the brain, Ube3a is an imprinted gene; only the maternal allele is expressed, even if it is mutated and the paternal allele is normal. This is the case in Angelman syndrome, a severe neurodevelopmental disorder caused by mutation or deletion of the maternal allele of Ube3a. Ube3a is imprinted only in the brain, though; in other tissues, the paternal allele is expressed along with the maternal one.

This led Benjamin Philpot and his colleagues at UNC Chapel Hill to wonder: wouldn’t it be great if we could get the normal, paternal version of Ube3a to work in the brain—to unsilence it? Maybe this could help kids with Angelman syndrome.

To find a drug that might allow the paternal copy of Ube3a to be expressed, they first made mice in which only the paternal copy of the gene was linked to the gene for yellow fluorescent protein. They then isolated cortical neurons from these mice and exposed the neurons to a variety of chemicals. If any of these chemicals caused the cells to glow yellow, that meant that they allowed expression of the paternal UBE-3A-yellow fluorescent protein hybrid.

The scientists screened 2,306 different compounds, four times each. Most of the compounds have already been approved for use in humans, so if the researchers found anything promising, clinical trials would be expedited. They concentrated on agents known to be active in the central nervous system and those that are known to interfere in epigenetic regulation (like the methylation often used in imprinting). Unfortunately, none of these activated the paternal UBE-3A-yellow fluorescent protein hybrid.

But there was one compound that unsilenced the gene: topotecan, a drug that is part of a class called topoisomerase inhibitors. Topoisomerases are enzymes that alleviate the stress on a DNA double helix that occurs when the two strands are pulled apart, as they are when a gene is expressed.

Once topotecan was identified, the researchers went on to show that other topoisomerase-inhibiting drugs, both those structurally similar to topotecan and those with different structures, could unsilence paternal Ube3a. They then injected topotecan into mouse brains to demonstrate that it could work in vivo, and not just in tissue culture dishes. They found that paternal Ube3a expression persisted in spinal cord neurons for up to 12 weeks after drug treatment; this long lasting effect is significant because genetic imprinting is thought to be established during specific points in embryonic development and then maintained for life.

Paternal Ube3a is normally silenced by what's called an antisense transcript—a piece of RNA that covers up the gene to prevent its expression. (This antisense transcript is not made from the maternal chromosome.) Topotecan worked on the paternal chromosome, dampening antisense transcription there.

Inherited neurological disabilities have been extremely difficult to treat. In Angelman’s syndrome, the brain architecture seems normal at birth, so it is possible that the restoration of normal gene expression could correct some of the pathologies. Topotecan is approved for use in people with cancer, and it has been shown to be well tolerated in children. Hopefully, it could be therapeutically valuable for those with Angelman’s syndrome; it has definitely been valuable in showing how a dormant but functional gene can be reactivated.

12 Reader Comments

Ouch, 2,305 negative results. I know negative results are supposed to be just as important as positive ones, but that's a lot of days when you go home wondering if you'll have anything to show for your efforts. Molecular biology is brutal.

Ouch, 2,305 negative results. I know negative results are supposed to be just as important as positive ones, but that's a lot of days when you go home wondering if you'll have anything to show for your efforts. Molecular biology is brutal.

Massive shotgun searches in the initial phase of drug searches are normal. The real heartbreak is when you find something that looks like a winner in initial testing but ends up having a showstopper problem that's only discovered after you've spent years of your life working on it.

Ouch, 2,305 negative results. I know negative results are supposed to be just as important as positive ones, but that's a lot of days when you go home wondering if you'll have anything to show for your efforts. Molecular biology is brutal.

Massive shotgun searches in the initial phase of drug searches are normal. The real heartbreak is when you find something that looks like a winner in initial testing but ends up having a showstopper problem that's only discovered after you've spent years of your life working on it.

I know people that this has happened to: years of work and promising results just to learn that what they were working on was a dud They ended up being very disappointed, burnt out. These are people who were putting 12+ hours of work, 7 days a week, for many years. Some lived in the lab for days during experiments. Yup, brutal. That's why I get even more upset by idiots doubting science. They have no clue how much work goes into this stuff. This is not some lame 9-to-5 job.

They quit research and got jobs as teachers or went to work for the biotech industry, where money was better anyway, but their academic carriers and dreams were gone.

I am the parent of AS child. My wife and I NEVER thought we would hear the words Angelman Syndrome and treatment in the same sentence. The AS community is buzzing about this research. Just the thought that in perhaps 5 or 6 years a therapy could allow our child to begin living a more normal life virtually brings tears to my eyes. I can't imagine a better holiday gift than this news.

This is all very exciting....my son has a UBE3a mutation....he is missing a little part of the gene and it has been explained to me that the rest of the gene is all in place after this missing part....I think they call it not being trunkated? Anyway....I find it especially interesting in his case b/c his UBE3A mutation is so small and he seems to be cognitively higher functioning than many of his AS peers.....are there any plans for future drug trials?